Definition

We report on two stillborn sisters with generalized hydrops, campomelia, cervical lymphocele, and polycystic dysplasia of the kidney, liver, and pancreas. This syndrome conforms to that first described by Cumming in 1986. These cases in the same family with likely parental consanguinity supports the notion that Cumming syndrome has an autosomal recessive pattern of inheritance.

Case report

We report the case of a patient, G2P1, with unremarkable medical history. Her first child is normal. Consanguinity with the father of the fetus is probable. She presented late to care at 28 weeks with a second pregnancy. On ultrasound, we discovered anhydramnios, IUGR, visceral situs inversus (Image A), and an isolated ventriculoseptal defect (Image B). The kidneys were hyperechoic with loss of corticomedullary differentiation. The bladder was not visualized; rocker-bottom feet were suspected. Fetal MRI was done, confirming these anomalies. Amniocentesis was performed but it was impossible to obtain amniotic fluid. Upon cordocentesis under sonographic guidance, a karyotype of 46, XX was found. The patient was informed of the prognosis and chose to interrupt the pregnancy. Necropsy was refused. Serologic analysis was unremarkable.

Fetal weight was 1430 gm. Gross pathological analysis showed a narrow thorax, small, low-set ears, and a short philtrum. The uvula was absent; there was no cleft lip nor cleft palate. The feet were dorsiflexed on the legs; the femoral bones and tibias were bowed. The digits were long. Considering these findings it was difficult to reach a diagnosis.

Images A and B. (Fetus 1).Image A (left) - Transverse thoracic section at 28 weeks, showing the heart with VSD (the images are suboptimal due to anhydramnios). Image B (right) - Parasagittal section at 28 weeks showing the heart and great vessels.

The patient was referred to us to us the next year with a third pregnancy at 26 weeks. On sonography the only visualized anomaly was a small renal cyst. We saw the patient again at 35 weeks GA when she had uterine contractions. On sonography we now saw IUGR, anhydramnios, and a small bladder with two umbilical arteries (Image 2A, 2B). The stomach was not seen. The kidneys were disparate in size. The right kidney was hyperechoic with loss of corticomedullary differentiation (Image 1A, 1B, 1C, 1D, 1E). The hypoplastic left kidney was micropolycystic (Image 3A, 3B, 3C). There was situs solitus, right myocardial hypertrophy (Image 4A, 4B, 4C), and a hyperechoic, dysplastic tricuspid valve. The left ventricle was hypoplastic. The femurs were curved.

The patient was informed about the probable recurrence of the “unknown syndrome” in her prior pregnancy and about fetal prognosis. She delivered at 37 weeks GA; the fetus weighed 3060 g, was anuric, and died on the third day of life.

Pathophysiologic analysis was agreed to. Hypertelorism, dysplastic ears, and narrow forehead were seen. The thorax was narrow, with twelve ribs seen on radiography. There was campodactyly with a hypoplastic fifth digit as well as platyspondyly. Renal histology showed a micropolycystic cortex and medullary dystrophy. There was intrahepatic biliary hypoplasia. Bilateral bowed femurs were seen.

Cardiac abnormalities included intraventricular wall hypertrophy with obstructive cardiomyopathy. There was an intraventricular septal defect. The tricuspid and mitral valves were normal, but the sigmoid, aortic, and pulmonary valves were thick and dysplastic.

These anomalies in the second and third pregnancies of our patient seemed to indicate an autosomal recessive syndrome, which we suspected to be Cumming syndrome.

History

Cumming Syndrome History

In 1986 Cumming et al described a fetus affected by several anomalies: campomelia, cervical lymphocele, polysplenia, short intestines, and polycystic kidneys, liver, and pancreas. The parents were consanguineous, suggesting autosomal recessive transmission.

In 1991, Urioste reported two similar cases with cervical lymphocele, multicystic dysplastic kidneys, and campomelia. The first infant died after five minutes of life and the second after an hour of life. The parents came from the same village in Spain.

Tricoire et al in 1993 described what also seems to be a case of Cumming syndrome, as did Ades et al in 1994. Dibbern, in 1998, reported two cases. Also in 1998, Perez Del Rio et al described two sisters affected by hydrops, campomelia, and polycystic dysplasia of the kidneys, liver, and pancreas. Both sisters died shortly after birth. Ming et al (1997) reported another case with campomelia, visceral heterotaxy with polysplenia, and multicystic dysplastic kidney disease.

Reunion Island History

Reunion Island (Ile de la Reunion), France, is located in the Indian Ocean near Madagascar in the Mascareigne archipelago. It is a small volcanic island of about 720,000 inhabitants. It is over 2500 km2 with a mountain range whose highest peak is 3069 meters, the hook of Snows. The Portugese discovered the island in 1513. From the 17th to the 19th centuries, French immigration was supplemented by an influx of Africans, Chinese, Malays, and Indians from Malabar. Reunion Island was an important stopover on the East Indies trade route until the opening of the Suez Canal in 1869.

Reunion Island is nicknamed “the island of intensity;” it is a paradise of variety. Its volcano, “le piton de la Fournaise,” is one of the most active volcanoes worldwide. There are three isolated regions on the island, Mafate, Cilaos, and Salazy. They are surrounded by mountains. In these areas there are tiny villages with no roads; only foot travel is possible, leading to isolation and consequently a high incidence of consanguinity.

Our patient and her husband were from Mafate, one of these isolated regions.

Prevalence

According to Urioste et al, the prevalence of Cumming syndrome at birth is estimated to be 0.027:10,000 births. According to Lazebnick, Cumming syndrome affects male fetuses more often than female.

Etiology

Cumming syndrome is genetic. Autosomal recessive transmission seems likely, as all cases in the literature feature parental consanguinity. Our two cases seem to be the eleventh and twelfth cases of Cumming syndrome reported in the literature to date.

Pathogenesis

Exact pathogenesis of Cumming syndrome is unknown; the responsible gene has not yet been identified.

Sonographic findings

Cumming described specific findings: general edema, cervical hygroma, cleft palate; short limbs with bowing of lower-extremity long bones. Polysplenia, cecal atresia, and short intestines were also described by Ming. Ming et al also described a fetus with Cumming syndrome, tetramelic campomelia, and bilateral rocker-bottom feet.

In Cumming syndrome, the thorax is often narrow. Cardiac anomalies such as anomalous pulmonary venous return, persistent left superior vena cava, and dextrocardia may be seen. One of Ming’s cases presented with two left-sided auricles, left ventricular hypoplasia, and left isomerism (polysplenia). In another case of Cumming syndrome, Ming described anomalous pulmonary lobulation.In our first case, the fetus had total visceral situs inversus.

Multicystic polycystic kidney disease is reported in all cases of Cumming syndrome. The polycystic hyperechogenic kidneys characteristic of Cumming syndrome are featured in other syndromes.

Implications for targeted examinations

Suspicion for Cumming syndrome is raised on visualization of the constellation of multicystic kidneys, bowed femurs, cardiac anomalies, visceral heterotaxy, and/or cervical hygroma. Fetal akaryotypia must be assessed, as it will be normal in cases of Cumming. Genetic consultation is indispensable.

Differential diagnosis

Cumming syndrome can be differentiated from several osteochondrodysplasias:

Campomelic dysplasia is the most important osteochondrodysplasia to rule out. It is characterized by scapular and iliac wing dysplasia, and especially by curved bowed lower-extremity long bones. A narrow, bell-shaped thorax may be seen. Most infants die of pulmonary hypoplasia in early infancy. 50% of campomelic dysplasia cases are phenotypic females with a 46, XY karyotype. All cases present with an irregularity of the SOX-9 gene. Campomelic dysplasia does not usually present with multicystic dysplastic kidney disease. It can be differentiated from Cumming syndrome because in campomelic dysplasia, all of the lower-extremity long bones are curved, whereas in Cumming syndrome, only the femurs are affected.

Osteogenesis imperfecta type II and type III are eliminated in the differential because the long bones are always shortened, and fractures as well as various healing bony calluses present.

Kyphomelic dysplasia or diastrophic dysplasia, hypophosphatasia, and Larsen syndrome: These are easily eliminated from the differential, as none present with renal anomalies.

Stuve-Wiedemann syndrome (which often features renal, pancreatic, and hepatic dysplasia) is excluded because of absence of campomelia.

Prognosis

Cumming syndrome prognosis is directly linked to the severity of renal dysfunction, as well as to the developmental beginnings of renal dysplasia in the pregnancy. The prognosis also depends on associated cardiac anomalies and thoracic hypoplasia. Among all the cases we researched in the literature, we found no infant with Cumming syndrome who survived the immediate postnatal period.

Conclusion

Prenatal discovery of Cumming syndrome is difficult for two reasons: Cumming syndrome is extremely rare; and second, because of phenotypic likenesses, Cumming syndrome is frequently confused with campomelic dysplasia, as demonstrated by Watiker et all (2005). Mutation SOX-9 is pathognomonic for Cumming syndrome. Campomelic dysplasia is usually sporadic with rare autosomal dominant transmission, whereas Cumming syndrome has autosomal recessive transmission with a recidivism risk of 25% in the same family.

Upon suspicion of Cumming syndrome, in particular in the same family, it is advisable to recommend medical interruption of pregnancy. If the patient wishes to continue pregnancy, amniocentesis (or cordocentesis, if there is not enough amniotic fluid) and renal biopsy in utero may be recommended.